PRNP and prion disease: The following discussion is based on the consideration of prion diseases into two broad categories: acquired (when the source of prions is an external one that seeds the misfolding of the host protein) versus spontaneous (where the misfolding event occurs spontaneously in an individual either idiopathic in nature or favoured by the host genotype, in terms of the presence of a pathogenic mutation on the PRNP gene and its expression levels).